One of the most prevalent manifestations of chronic inflammation is Inflammatory Bowel Disease (IBD), which principally comprises Crohn's Disease (CD) and Ulcerative Colitis (UC). IBD affects the colon, small intestine, or both and is characterized by chronic recurrent bowel ulceration (1). The IBD pathogenesis likely involves the complex interaction between genetic, environmental, and immunological factors resulting in an upsetting and exaggerated intestinal inflammatory response to intestinal microbiota in vulnerable individuals (2, 3). A significant part of disability and malfunctioning that occurs in chronic health problems is associated with psychological disorders (4). Psychological disorders can affect the symptomatic disease courses and increase inflammation. Anxiety and depression are known as comorbidities in IBD patients (5). They are related to the Hypothalamic-Pituitary-Adrenal (HPA) axis activation and increased circulating cortisol levels. Lengthened activation of the HPA axis, as occurs in prolonged stress or chronic inflammation, including IBD, causes chronic cortisol level elevation, leading to reduced sensitivity of glucocorticoid receptors. Reduced glucocorticoid receptor sensitivity can enhance immunological responses and augment inflammation (6, 7). On the other hand, remedies with corticosteroids can induce psychiatric symptoms (7). The findings declare that the depression prevalence is between 15% and 25%, with possibly lower rates in UC patients than in those who suffer from CD (8, 9). Anxiety is even more rampant, with rates of nearly 30% in IBD patients (10). The rates of anxiety and depression have been higher pending periods of disease flare-up (11). Interestingly almost three-fourths of anti-depressant medications are prescribed without companioning psychiatric indications (12). Approximately 30% of IBD sufferers administrate anti-depressant medications for mental health, bowel symptoms, or both (13). Despite the NICE guideline, which suggests taking anti-depressants for the long term when depression is accompanied by a chronic physical ailment such as IBD or cancer (14), none of the Crohn's and Colitis councils have officially ratified anti-depressants as a routine regimen for IBD patients. However, some physicians empirically prescribe them for two aims (15). First, they recommend anti-depressants to rectify functional bowel consequences such as pain (16). A qualitative study appraising the use of anti-depressants for IBD patients demonstrated that most gastroenterology specialists (78%) had treated the patients for symptoms palliation with anti-depressants as adjunctive therapy, especially for pain (17). Second, they claim anti-depressants profitability since they can ameliorate the psychiatric comorbidities in IBD (18). However, findings regarding the direct benefit of anti-depressants on IBD, regardless of their impact on psychiatric comorbidities, are restricted, and existing ones are controversial, especially with current investigations. Hence, in this review, the molecular mechanisms and clinical evidence are scrutinized and integrated to clarify the proper decision-making about Selective Serotonin Reuptake Inhibitor (SSRI) prescribing. This study focused on SSRIs among all the anti-depressant classes since each class's proficiency differs. SSRIs have been the most common anti-depressants since 1974 (19) when they were introduced, so debating on this group is more necessary. Functions and pathways should be discussed to recognize better what is happening during the SSRI treatment in IBD.